The possibility that effector T cells can be converted into forkhead box P3+ regulatory T cells (Tregs) has potential therapeutic implications. To analyze the relationship between Th1 effectors and Tregs, we have used a model of systemic autoimmunity in which both effector and Tregs arise from a single population specific for a transgene-encoded systemic protein. In vitro, the presence of IFN-γ inhibits Treg generation during activation. Using IFN-γ reporter mice, we demonstrate that IFN-γ–producing cells tend not to develop into Tregs, and Th1 priming of T cells prior to cell transfer limits the number of forkhead box P3+ T cells generated in vivo. Moreover, transfer of IFN-γ−/− or STAT1−/− T cells resulted in an increase in the number of Tregs. These data support a role for Th1 effector molecules and transcription factors in the control of peripheral Treg generation and demonstrates the limited plasticity of Th1 populations.

Objective. Monocyte chemoattractant protein 1 (MCP-1; CCL2) has been implicated in the pathogenesis of fibrotic diseases and is up-regulated in patients with systemic sclerosis (SSc). The aim of the present study was to examine the mechanisms by which MCP-1 mediates its profibrotic effects in the setting of SSc.Methods. The expression of receptors for MCP-1 on dermal fibroblasts was analyzed by real-time polymerase chain reaction and fluorescence-activated cell sorting. The ability of extracellular matrix proteins to bind and release MCP-1 was quantified by enzymelinked immunosorbent assay. Th0 cells were isolated using a magnetic-activated cell sorting system and were stimulated twice in the presence of MCP-1. The synthesis of collagen was measured using the Sircol collagen assay kit.Results. The glycosaminoglycan chondroitin sulfate, but not fibronectin or collagens, bound and released MCP-1 in a time-dependent manner. MCP-1 that was released from chondroitin sulfate induced the differentiation of interleukin-4 (IL-4)-producing T cells in a dose-dependent manner. In turn, dermal fibroblasts from patients with SSc expressed IL-4 receptor, and stimulation with IL-4 significantly increased the production of collagen in dermal fibroblasts. In contrast, CCR2a and CCR2b, as well as D6 and US28 (other potential receptors of MCP-1), were not detectable in SSc and normal fibroblasts, and their expression was not induced by platelet-derived growth factor, IL-1␤, or IL-4. In addition, MCP-1 had no direct effects on collagen production by fibroblasts.Conclusion. MCP-1 has no direct effects on dermal fibroblasts but contributes to fibrosis in patients with SSc by inducing the differentiation of IL-4-producing T cells. Because MCP-1 has both proinflammatory and profibrotic effects, pharmacologic targeting of MCP-1 could be a promising therapeutic approach in SSc.Systemic sclerosis (SSc) is a chronic fibrotic disorder of unknown etiology that affects the skin and a variety of internal organs. In the early stages of disease, inflammatory infiltrates are a histopathologic hallmark of SSc. The inflammatory infiltrates are T cell dominated and localized predominantly in perivascular regions. Later stages of the disease are characterized by an excessive accumulation of extracellular matrix components. The extracellular matrix components are produced by activated fibroblasts and include glycosaminoglycans (GAGs) such as chondroitin sulfate, fibronectin, type I collagen, type III collagen, type VI collagen, and type VII collagen (1,2).The mechanisms leading to the activation of

Transfer of antigen-specific T cells into antigen-expressing lymphopenic recipients leads to the sequential generation of Th1 and Th17 effector and protective CD25+FoxP3+ regulatory cells in the periphery with surprisingly different kinetics. Such an experimental model is potentially valuable for defining the stimuli that regulate lineage decision and plasticity of various T cell effectors and peripheral regulatory T cells. Our studies have shown that IL-17 production occurs rapidly and declines within the first week with the appearance of IFN-γ producing T cells. Regulatory T cells appear during the recovery phase of the disease. The factors that mediate this complex differentiation originating from a starting naïve T cell population remain to be defined.

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